The present invention relates to a novel process for making geminal bisphosphonates. The process provides for bisphosphorylation using phosphorus trihalide, molten phosphorous acid as a reactant/solvent, and a base as an acid acceptor/solvent.
Polyphosphonic acids and their pharmaceutically-acceptable salts have been proposed for use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. In particular bisphosphonates, like ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), propane-3-amimo-1-hydroxy-1,1-diphosphonic acid (APD), dichloromethane diphosphonic acid (C12MDP), 3-amino-1-hydroxy-propylidene-diphosphonic acid. (PAMIDRONATE), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONATE) and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid (RISEDRONATE) have been the subject of considerable research efforts in this area. Paget""s disease and heterotropic ossification are currently successfully treated with EHDP. The diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in activity, bisphosphonates do not exhibit the same degree of activity and some have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or the negative side effects in humans.
Several methods for making bisphosphonates have been disclosed. For example, European Patent Application 0 494 644, Instituto Gentili and PCT application WO96/33199 disclose methods for making amino-bisphosphonates. However, just as there are differences in the activities of the different bisphosphonates, so too are there differences in the method of making these compounds. Depending on the reaction conditions, the viscosity of the reaction mixture and/or the formation of large amounts of elemental phosphorus by-products limit the scale on which the bisphosphorylation reaction can be readily carried out.
It is therefore desirable to use a scaleable process to produce geminal bisphosphonates that achieves high yields with little residual elemental phosphorous by-products and that can be safely practiced on the commercial scale.
The present invention is directed to a process for making geminal bisphosphonates of the general formula: 
wherein Q is oxygen, xe2x80x94NR4xe2x80x94, sulfur, selenium, or a single bond; m+n is an integer from 0 to about 5, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine; R1 is independently hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each R2 is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R3 is one or more substituents selected from the group consisting of hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R4 is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl; resulting from bisphosphorylation of an aminocarboxylic acid in the presence of phosphorus trihalide, molten phosphorous acid and base such as morpholine to form a geminal bisphosphonate.
The present invention is directed to a novel process for making geminal bisphosphonates. Said process involves the use of molten phosphorous acid, an amino carboxylic acid, phosphorous trihalide, and base in the bisphosphorylation step. The reaction is carried out at a temperature of from about 45xc2x0 C. to about 90xc2x0 C., preferably from about 55xc2x0 C. to about 85xc2x0 C., more preferably from about 60xc2x0 C. to about 75xc2x0 C. The presence of an additional solvent is optional. Particularly preferred geminal bisphosphonates made by this process are 1-hydroxy-2-(3-pyridinyl)ethylidine bisphosphonic acid, 4-amino-1-hydroxybutylidene-1,1-bisphonic acid, and 3-amino-1-hydroxypropylidene-diphosphonic acid. Most preferred is risedronate, 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonicacid.
The following is a list of definitions for terms used herein:
As used herein, xe2x80x9calendronatexe2x80x9d denotes 4-amino-1-hydroxybutylidene-1,1-bisphonic acid.
As used herein, xe2x80x9calkenylxe2x80x9d means a hydrocarbon substituent with one or more double bonds, straight or branched chain, unsubstituted or substituted.
As used herein, xe2x80x9calkoxyxe2x80x9d means a substituent having the structure Q-O-, where Q is alkyl or alkenyl.
As used herein, xe2x80x9calkylxe2x80x9d means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
As used herein, xe2x80x9calkylthioxe2x80x9d means a substituent having the structure Q-S-, where Q is alkyl or alkenyl.
As used herein, xe2x80x9caminocarboxylic acidxe2x80x9d is a saturated or unsaturated substituted or unsubstituted alkyl with a carboxylic acid group attached to one end and an amine group either attached to one of the carbons of the alkyl chain or as a heteroatom in a saturated or unsaturated substituted or unsubstituted heterocyclic ring.
As used herein, xe2x80x9cbasexe2x80x9d means a basic reagent which is added to a reaction mixture to facilitate bisphosphorylation. Bases include organic and inorganic bases. Preferred bases include those which have easily filterable or otherwise removable salts. Specifically, preferred bases include N,N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and morpholine. The more preferred bases are triethylamine, trimethylamine, potassium carbonate, pyridine and morpholine. The most preferred base is morpholine. The base may be added as the free base or in its salt form.
As used herein, xe2x80x9cbiohydrolyzable esterxe2x80x9d is an ester moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
As used herein, xe2x80x9cbisphosphorylationxe2x80x9d is the chemical reaction resulting in the production of a product containing two phosphoryl groups on the same carbon.
As used herein, xe2x80x9ccarbocyclic ringxe2x80x9d is a saturated, unsaturated, or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms.
As used herein, xe2x80x9chalogenxe2x80x9d is a chloro, bromo, fluoro, or iodo atom radical. Bromo and chloro are the most preferred halogens.
As used herein, xe2x80x9cheterocyclic ringxe2x80x9d is a saturated, unsaturated, or aromatic, ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms.
As used herein, xe2x80x9cinorganic acidxe2x80x9d is a mineral acid such as sulfuric, nitric, hydrochloric, phosphoric, and phosphorous.
As used herein, xe2x80x9cmethylenexe2x80x9d is a xe2x80x94CH2xe2x80x94 radical.
As used herein, xe2x80x9cmolten phosphorous acidxe2x80x9d means phosphorous acid heated to from about 45xc2x0 C. to 95xc2x0 C., preferably from about 55xc2x0 C. to about 85xc2x0 C., more preferably from about 60xc2x0 C. to about 75xc2x0 C.
As used herein, xe2x80x9corganic acidxe2x80x9d is an organic carboxylic acid, such as formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, and methane sulfonic acid.
As used herein, xe2x80x9cphosphorus trihalidexe2x80x9d is a tri-halogen substituted phosphorus. The more preferred phosphorus trihalide is phosphorus oxychloride, phosphorus oxybromide, phosphorus tribromide or phosphorus trichloride. Most preferred is phosphorus trichloride.
As used herein, xe2x80x9cPamidronatexe2x80x9d denotes 3-amino-1-hydroxypropylidene-diphosphonic acid.
The term xe2x80x9crisedronatexe2x80x9d, as used herein, denotes and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonicacid and has the following structure: 
The compound risedronate is further described in U.S. Pat. No. 5,583,122, Benedict et al., assigned to the Procter and Gamble Co., issued Dec. 10, 1996, and xe2x80x9cAn American Conference, Bisphosphonates: Current Status and future Prospects,xe2x80x9d The Royal College of Physicians, London, England, May 21-22, 1990, organized by IBC Technical Services, both references hereby are incorporated by reference.
The term xe2x80x9cbisphosphonate active ingredientxe2x80x9d includes the bisphosphonate free acid, bisphosphonate salts, and bisphosphonate esters, or any mixture thereof. Any pharmaceutically-acceptable, non-toxic salt or ester of bisphosphonate may be used as the risedronate active ingredient in the novel oral dosage forms of the present invention. The salts of bisphosphonate may be acid addition salts, in particular the hydrochloride, but any pharmaceutically-acceptable, non-toxic organic or inorganic acid salt may be used. In addition, salts formed with the phosphonic acid group may be used, including, but not limited to alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg) the Ca and Na salts being preferred.
Particularly, other esters of bisphosphonate which are suitable for use as the active ingredient herein are straight chain or branched chain C1-C18 alkyl esters, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl; straight chain or branched C2-C18 alkenyl, esters, including but not limited to vinyl, alkyl, undecenyl, and linolenyl; C3-C8 cycloalkyl esters, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl ester, including, but not limited to phenyl, toluyl, xylyl, and naphthyl; alicyclic esters, including, but not limited to, menthyl; and arylalkyl esters, including, but not limited to benzyl, and phenethyl.
As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (e.g. aminomethyl, etc.), cyano, halogen, alkoxy, alkoxyacyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
As used herein, xe2x80x9csolventxe2x80x9d, is a substance capable of dissolving another substance to form a uniform solution. The solvent may either be polar or non-polar. Solvents for the bisphosphorylation reaction include but are not limited to inorganic acids, organic acids, and organic bases.
The bisphosphorylation step of the present process invention is conducted such that the corresponding aminocarboxylic acid is dissolved in molten phosphorous acid and reacted with phosphorus trihalide in the presence of a base, where the base is preferably morpholine or pyridine. The reaction is carried out in the temperature range between about 45xc2x0 C. to about 90xc2x0 C., preferably between about 55xc2x0 C. to about 90xc2x0 C., more preferably between about 55xc2x0 C. to about 85xc2x0 C., and most preferably between about 60xc2x0 C. to about 75xc2x0 C. The process described herein is readily adapted to industrial production.
Without a solvent, such as excess phosphorous acid, and a base the reaction mixture would be very viscous. The phosphorous acid and bases added in the process act as a solvent to give a uniform reaction mixture or solution. The amount of phosphorus trihalide added in relation to the aminocarboxylic acid is from about 1.7 equivalent to about 2.5 equivalents, preferably about 2 equivalents. The amount of phosphorous acid and phosphorus trihalide should be controlled to avoid the formation of pyrophoric elemental phosphorus. Phosphorus trichloride reacts with phosphorous acid under the reaction conditions consuming some of the phosphorus trichloride and liberating hydrochloric acid gas. Generally, the amount of phosphorous acid added in relation to the amiocarboxylic acid is from about 1.5 to about 6 equivalents, preferably from about 2 to about 6 equivalents, more preferably from about 2 to about 5.5 equivalents, most preferably 5 equivalents. The base is added in an amount appropriate to achieve the desired viscosity. The amount of base added in relation to the phosphorous acid is from about 0.2 to 0.8 equivalents, more preferably from about 0.4 to about 0.6 equivalents. The process described herein is readily adapted to industrial production.
This process is illustrated by the following general scheme: 
wherein Q is oxygen, xe2x80x94NR4xe2x80x94, sulfur, selenium, or a single bond; m+n is an integer from 0 to about 5, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine; R1 is independently hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,; each R2 is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R3 is one or more substituents selected from the group consisting of hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted and unsubstituted arly, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R4 is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl; resulting from bisphosphorylation of an aminocarboxylic acid in the presence of phosphorus trihalide, molten phosphorous acid and base such as morpholine to form a geminal bisphosphonate.
The following non-limiting examples illustrate the processes of the present invention.